Familial Alzheimer's disease associated with heterozygous NPC1 mutation.

INTRODUCTION: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation. METHODS: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. RESULTS: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1, shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3ß,5α,6ß-triol. DISCUSSION: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.

Dosimetry and safety of 177Lu PSMA-617 along with polyglutamate parotid gland protector: preliminary results in metastatic castration-resistant prostate cancer patients.

PURPOSE: Radioligand therapy (RLT) with 177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate cancer (mCRPC). The present study was designed to define the safety and initial response to a minimal effective injected activity/cycle of 177Lu-PSMA-617 in mCRPC patients. New protective agents for salivary glands and kidney were co-administered and dosimetry was carried out. PATIENTS AND METHODS: A prospective single-arm, open label phase II study on mCRPC was activated at our institute in April 2017. Patients with histologically confirmed advanced mCRPC previously treated with standard life-prolonging agents were enrolled. Folic polyglutamate tablets were orally administered as parotid gland protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake before the injection of 3.7-5.5 GBq of 177Lu-PSMA-617 repeated four times at interval of 8 weeks. The adsorbed dose calculation was performed with MIRD formalism (OLINDA/EXM software). The Bryant and Day design was used to estimate the sample size taking account of both activity and toxicity. RESULTS: Forty-three eligible patients were evaluated for toxicity and initial response. Dosimetry was carried out in 13 patients. Two (4.8%) patients had G3 and 8 (19.5%) had G2 hematological toxicity. Only 3 (6.9%) patients had mild G1 salivary gland toxicity and 8 (19.5%) had G1 renal toxicity. A decrease of ≥ 30% in prostate-specific antigen (PSA) was achieved after the first cycle in 17 (40.5%) patients, of whom 13 had a PSA decline of >50% after the second cycle. The median adsorbed doses were 0.65 mGy/MBq (range 0.33-2.63) for parotid glands, 0.42 mGy/MBq (0.14-0.81) for kidneys, 0.036 mGy/MBq (0.023-0.067) for red marrow, and 0.038 mGy/MBq (0.018-0.135) for the whole body. CONCLUSION: In advanced, heavily pre-treated mCRPC patients, 3.7 GBq/cycle of 177Lu-PSMA-617 was safe and produced early biochemical and imaging responses at PSMA whole-body scan post injection. Dosimetry of salivary glands suggests that the co-administration of polyglutamate tablets may reduce salivary gland uptake. CLINICAL TRIAL REGISTRATION: EU Clinical Trials Register No.: 2016-002732-32; NCT03454750. Collection and assembly of data: April 2017 and February 2019.

Dosimetry of 177Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet Administration: Preliminary Results of EUDRACT/RSO 2016-002732-32 IRST Protocol.

Radio-ligand therapy (RLT) with177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53⁻85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16⁻24 h, 36⁻48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6⁻60.7) for PGs, 31.4 h (12.2⁻80.6) for kidneys, 8.2 h (2.5⁻14.7) for RM and 40.1 h (31.6⁻79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33⁻2.63) for PGs, 0.70 mGy/MBq (0.26⁻1.07) for kidneys, 0.044 mGy/MBq (0.023⁻0.067) for RM and 0.04 mGy/MBq (0.02⁻0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake.

Rethinking Tako-tsubo Cardiomyopathy: The Contribution of Myocardial Pathology and Molecular Imaging.

BACKGROUND: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive. OBJECTIVE: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. METHODS: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. RESULTS: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determinant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardial perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. CONCLUSION: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamineinduced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.

[18F]-FDG-PET/CT Correlates With the Response of Radiorefractory Thyroid Cancer to Lenvatinib and Patient Survival.

CONTEXT: 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ([18F]-FDG-PET/CT)-positive metastatic lesions in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have a poor prognosis and lenvatinib represents the best therapy. OBJECTIVE: We investigated the role of [18F]-FDG-PET/CT in the evaluation of metabolic response and prediction of the outcome of RAI-R DTC patients treated with lenvatinib. METHODS: Patients (n = 33) with progressive metastatic RAI-R DTC who were treated with lenvatinib were investigated at baseline and during follow-up with biochemical (thyroglobulin and thyroglobulin antibodies), morphological (whole-body CT scan) and metabolic ([18F]-FDG-PET/CT) evaluation. RESULTS: Nineteen (57.6%) patients showed the greatest metabolic response at the first [18F]-FDG-PET/CT scan, performed after 4 weeks of lenvatinib, while 5/33 (15.1%) patients had this response later. Moreover, 66.7% of patients had both a metabolic response at the first [18F]-FDG-PET/CT scan and a morphological response at the first CT scan. We observed a correlation between the metabolic response at [18F]-FDG-PET/CT scan performed after 4 weeks of treatment and the biochemical response at the same time in 60.6% of patients. The median overall survival (OS) was significantly longer in patients with either a metabolic response at last [18F]-FDG-PET/CT (40.00 vs 8.98 months) or a morphological response at last CT scan (37.22 vs 9.53 months) than in those without response. Moreover, the OS was longer in patients with a metabolic response at [18F]-FDG-PET/CT performed after 4 weeks of treatment (36.53 vs 11.28 months). CONCLUSIONS: Our data show that [18F]-FDG-PET/CT can early predict the response to lenvatinib and correlates with the OS of RAI-R DTC patients treated with this drug.

A Whole Body Dosimetry Protocol for Peptide-Receptor Radionuclide Therapy (PRRT): 2D Planar Image and Hybrid 2D+3D SPECT/CT Image Methods.

Peptide-receptor-radionuclide-therapy (PPRT) is a targeted therapy that combines a short-range energy radionuclide with a substrate with high specificity for cancer cell receptors. After injection, the radiotracer is distributed throughout the entire body, with a higher uptake in tissues where targeted receptors are overexpressed. The use of beta/gamma radionuclide emitters enables therapy imaging (beta-emission) and post-therapy imaging (gamma-emission) to be performed at the same time. Post-treatment sequential images permit absorbed dose calculation based on local uptake and wash-in/wash-out kinetics. We implemented a hybrid method that combines information derived from both 2D and 3D images. Serial whole-body images and blood samples are acquired to estimate the absorbed dose to different organs at risk and to lesions disseminated throughout the body. A single 3D-SPECT/CT image, limited to the abdominal region, overcomes projection overlap on planar images of different structures such as the intestines and kidneys. The hybrid 2D+3D-SPECT/CT method combines the effective half-life information derived from 2D planar images with the local uptake distribution derived from 3D images. We implemented this methodology to estimate the absorbed dose for patients undergoing PRRT with 177Lu-PSMA-617. The methodology could, however, be implemented with other beta-gamma radiotracers. To date, 10 patients have been enrolled into the dosimetry study with 177Lu-PSMA-617 combined with drug protectors for kidneys and salivary glands (mannitol and glutamate tablets, respectively). The median ratio between kidney uptake at 24 h evaluated on planar images and 3D-SPECT/CT is 0.45 (range:0.32-1.23). The comparison between hybrid and full 3D approach has been tested on one patient, resulting in a 1.6% underestimation with respect to full 3D (2D: 0.829 mGy/MBq, hybrid: 0.315 mGy/MBq, 3D: 0.320 mGy/MBq). Treatment safety has been confirmed, with a mean absorbed dose of 0.73 mGy/MBq (range:0.26-1.07) for kidneys, 0.56 mGy/MBq (0.33-2.63) for the parotid glands and 0.63 mGy/MBq (0.23-1.20) for submandibular glands, values in accordance with previously published data.

Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule: A 20-Year Retrospective Analysis.

PURPOSE: Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground-glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa. METHODS: Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL Tc-labeled human albumin macroaggregates (Tc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm-diameter collimated thoracoscopic gamma probe was resected. RESULTS: From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5-20 mm) with mean distance of 15 mm (range, 6-39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20-90 minutes), with an average time of 3 minutes (range, 1-5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%). CONCLUSIONS: This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection.

Radioguided Occult Lesion Localization: Technical Procedures and Clinical Applications.

PURPOSE: Regarding radioguided surgery, the concept of "radioguided occult lesion localization" (ROLL) is based on both preoperative interventional imaging and intraoperative radioguided detection of a clinically occult neoplastic lesion. METHODS: This methodology consists in the direct administration into the lesion of Tc-macroaggregated human albumin formed by relatively large particles retained at the injection site, which direct radioguided excisional biopsy. RESULTS: This modality has expanded from the classic application of ROLL for nonpalpable breast lesions to other tumors, such as solitary pulmonary nodules or recurrences from differentiated thyroid carcinoma. In 2011, in order to improve the classification of different radioguided surgical procedures, ROLL applications were included in the more complete concept of GOSTT (Guided intraOperative Scintigraphic Tumor Targeting). This concept was introduced to include the entire range of basic and advanced radioguided procedures necessary to supply a "road map" for the surgeon. CONCLUSIONS: The terms ROLL and GOSTT have further developed by incorporating novel modalities such as hybrid tracers for simultaneous fluorescence and radioactive signal detection and innovative navigation systems based on mixed-reality protocols.

Sentinel lymph node biopsy in breast cancer: a technical and clinical appraisal.

Breast cancer is the most common type of cancer diagnosed in women worldwide. Regional lymph node status is one of the strongest predictors of long-term prognosis in primary breast cancer. Sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection as the standard surgical procedure for staging clinically tumor-free regional nodes in patients with early-stage breast cancer. SLNB staging considerably reduces surgical morbidity in terms of shoulder dysfunction and lymphedema, without affecting diagnostic accuracy and prognostic information. Clinicians should not recommend axillary lymph node dissection for women with early-stage breast cancer who have tumor-free findings on SLNB because there is no advantage in terms of overall survival and disease-free survival. Starting from the early 1990s, SLNB has increasingly been used in breast cancer management, but its role is still debated under many clinical circumstances. Moreover, there is still a lack of standardization of the basic technical details of the procedure that is likely to be responsible for the variability found in the false-negative rate of the procedure (5.5-16.7%). In this article, we report the aspects of SLNB that are well established, those that are still debated, and the advancements that have taken place over the last 20 years. We have provided an update on the methodology from both a technical and a clinical point of view in the light of the most recent publications.

Sentinel Lymph Node Biopsy in Cutaneous Melanoma: Standard and New Technical Procedures and Clinical Advances. A Systematic Review of the Literature.

Melanoma is an important public health problem, and its incidence is increasing worldwide. The disease status of regional lymph nodes is the most important prognostic factor in early-stage melanoma patients. Sentinel lymph node biopsy (SLNB) was introduced in the early 1990s as a less invasive procedure than complete lymph node dissection to allow histopathologic evaluation of the "sentinel lymph node" (SLN), which is the first node along the lymphatic pathway from a primary tumor. Sentinel lymph node biopsy has minimal complication risks compared with standard complete lymph node dissection. Currently, SLNB is the accepted method for staging patients with clinically node-negative cutaneous melanoma and provides the most powerful prognostic information by evaluating the nodal basin status. The current practice of SLNB consists of the injection of Tc-labeled radiopharmaceutical, preoperative lymphoscintigraphy with the possibility of using the SPECT/CT hybrid imaging, and intraoperative SLN localization using a handheld gamma probe with or without the use of blue dye. Recently, the SLN localization and detection have been enhanced with the use of new tracers and new intraoperative devices, which have demonstrated to be particularly useful in melanomas of the head and neck region and in area of complex anatomy. Despite these important advances in the technology and the increasing experience in SLN mapping, major research centers have reported a false-negative rate higher than 15%. This relatively high false-negative rate, greater than those reported in the initial validation studies, points out the importance for the nuclear medicine community to continuously improve their knowledge on the biological behavior of melanoma and to improve the technical aspects that may allow more precise staging. For the SLNB procedure to be accurate, it is of critical importance that all "true" SLNs are identified and removed for examination. The aim of this article is to provide general information about the SLNB procedure in clinical practice highlighting the importance of standardization and accuracy of SLN identification in the light of the most recent technical innovations.

Sentinel Lymph Node Biopsy in Breast Cancer: Indications, Contraindications, and Controversies.

Axillary lymph node status, a major prognostic factor in early-stage breast cancer, provides information important for individualized surgical treatment. Because imaging techniques have limited sensitivity to detect metastasis in axillary lymph nodes, the axilla must be explored surgically. The histology of all resected nodes at the time of axillary lymph node dissection (ALND) has traditionally been regarded as the most accurate method for assessing metastatic spread of disease to the locoregional lymph nodes. However, ALND may result in lymphedema, nerve injury, shoulder dysfunction, and other short-term and long-term complications limiting functionality and reducing quality of life. Sentinel lymph node biopsy (SLNB) is a less invasive method of assessing nodal involvement. The concept of SLNB is based on the notion that tumors drain in an orderly manner through the lymphatic system. Therefore, the SLN is the first to be affected by metastasis if the tumor has spread, and a tumor-free SLN makes it highly unlikely for other nodes to be affected. Sentinel lymph node biopsy has become the standard of care for primary treatment of early breast cancer and has replaced ALND to stage clinically node-negative patients, thus reducing ALND-associated morbidity. More than 20 years after its introduction, there are still aspects concerning SLNB and ALND that are currently debated. Moreover, SLNB remains an unstandardized procedure surrounded by many unresolved controversies concerning the technique itself. In this article, we review the main indications, contraindications, and controversies of SLNB in breast cancer in the light of the most recent publications.